title: The telomere-associated homeobox-containing protein TAH1/HMBOX1 participates in telomere maintenance in ALT cells.
abstract: The majority of cancer cells rely on elevated telomerase expression and activity for rapid growth and proliferation. Telomerase-negative cancer cells, by contrast, often employ the alternative lengthening of telomeres (ALT) pathway to maintain telomeres. ALT cells are characterized by long and dynamic telomeres and the presence of ALT-associated promyelocytic leukemia (PML) bodies (APBs). Previous work has shown the importance of APBs to the ALT pathway, but their formation and precise role remain unclear. Here, we demonstrate that a homeobox-containing protein known as HMBOX1 can directly bind telomeric double-stranded DNA and associate with PML nuclear bodies. Hence, we renamed this protein TAH1 for telomere-associated homeobox-containing protein 1. TAH1 knockdown significantly reduced the number of APBs and led to an increase in DNA damage response signals at telomeres. Importantly, TAH1 inhibition also notably reduced the presence of telomere C-circles, indicating altered ALT activity. Our findings point to TAH1 as a novel link between pathways that regulate DNA damage responses, PML nuclear bodies, and telomere homeostasis in ALT cells, and provide insight into how ALT cells may achieve sustained growth and proliferation independent of the telomerase.
authors.affiliation: Key Laboratory of Gene Engineering of the Ministry of Education, School of Life Sciences, Sun Yat-Sen University, Guangzhou 510006, China.
authors.forename: Xuyang
authors.initials: X
authors.lastname: Feng
authors.forename: Zhenhua
authors.initials: Z
authors.lastname: Luo
authors.forename: Shuai
authors.initials: S
authors.lastname: Jiang
authors.forename: Feng
authors.initials: F
authors.lastname: Li
authors.forename: Xin
authors.initials: X
authors.lastname: Han
authors.forename: Yang
authors.initials: Y
authors.lastname: Hu
authors.forename: Dan
authors.initials: D
authors.lastname: Wang
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhao
authors.forename: Wenbin
authors.initials: W
authors.lastname: Ma
authors.forename: Dan
authors.initials: D
authors.lastname: Liu
authors.forename: Junjiu
authors.initials: J
authors.lastname: Huang
authors.forename: Zhou
authors.initials: Z
authors.lastname: Songyang
mesh_terms: D002460:Cell Line; D049109:Cell Proliferation; D004247:DNA / Q000378:metabolism; D004249:DNA Damage / Q000235:genetics; D004260:DNA Repair / Q000235:genetics*; D057809:HEK293 Cells; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000235:genetics / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D009369:Neoplasms; D034622:RNA Interference; D034741:RNA, Small Interfering; D019098:Telomerase / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D016615:Telomere / Q000378:metabolism*; D059505:Telomere Homeostasis / Q000235:genetics*
chemical_list: C512050:HMBOX1 protein, human; D018398:Homeodomain Proteins; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering; D004247:DNA; D019098:Telomerase
keywords: ALT pathway; Alternative lengthening of telomeres; DNA damage response; HMBOX1; Homeobox; TAH1; Telomere